It is known that at least some tumor cells are deficient in superoxide dismutase (SOD) activity, and SOD mimetics have been suggested in treating metastases. See, for example, Simic, M. G., et al., “Oxygen Radicals in Biology and Medicine,” Basic Life Sciences, Vol. 49, Plenum Press, N.Y. and London (1988); Weiss, J. Cell. Biochem. (1991) Suppl. 15C, 216 Abstract C110; Petkau, A., Cancer Treat. Rev. (1986) 13:17-44; McCord, J. M., J. Free Rad. Biol. Med. (1986) 2:307-310; and Bannister, J. V., et al., Crit. Rev. Biochem. (1987) 22:111-180.
In addition, a wide variety of chemotherapeutic agents are known, and the effects of the chemotherapeutic agents described herein have been disclosed. For example, it is known that gemcitabine is incorporated into RNA and DNA of tumor cell lines and that it is active against murine colon tumors, among others (see, e.g., Ruiz van Haperen, V. W., et al., Biochem. Pharmacol. (1993) 46:762-766 and Veerman, G., et al., Cancer Chemother. Pharmacol. (1996) 38:335-342). Combination treatment using gemcitabine with Imatinib mesylate enhances the therapeutic effects in human malignant mesothelioma xenografts, as described by Bertino, P., et al., Clin. Cancer Res. (2008) 14:541-548.
Various superoxide dismutase mimetics are also known in the art. For example, manganese and iron complexes of pentaazacyclopentadecane ligands are described in U.S. Pat. Nos. 5,610,293; 5,637,578 and 5,874,421, among others. These patents indicate that these particular superoxide dismutase mimetics are useful in treating metastases.
In addition, it has been reported that combination treatments of the superoxide dismutase mimetic KM4403 with interleukin-2 (IL-2) potentiates the antitumor effect of IL-2. See, Samlowski, W. E., et al., Nature Medicine (2003) 9:750-755.